Tumor hypoxia has been recognized as a hindrance to successful radiation therapy for over 50 years. The search for small molecules to act as oxygen mimetics and selectively sensitize hypoxic tumors to radiotherapy has had many worthy candidates in the past, but none have been successful in Phase III clinical trials. In addition, attempts to overcome hypoxia by delivering more oxygen to the tumor, however, have been clinically disappointing, largely due to the functional limitations of the tumor vasculature. Increasing systemic oxygen delivery does not result in increased tumor oxygenation. Instead of reducing hypoxia by increased delivery of oxygen, this application proposes to limit hypoxia by reducing oxygen consumption within the tumor. If the supply of oxygen delivered to the tumor is constant, then transient reduction in demand will result in increased tumor oxygenation. We have identified several commonly prescribed drugs (papaverine is the lead compound) that dramatically reduce mitochondrial function in vitro. We propose to test the hvpothesis that pharmacologic down regulation of mitochondrial metabolism will reduce cellular demand for oxygen and result in decreased tumor hypoxia and radiosensitization of model tumors. This approach will be especially effective when added to hypofractionated radiation protocols where oxygen enhancement can result in a profound increase on overall tumor cell killing. We have organized this proposal into the following four specific aims. 1) Determine the effective concentration of two mechanistically different, FDA approved drugs to inhibit the mitochondrial function of a panel of cancer cell lines in vitro. 2) Quantify the biochemical effect of drug treatment on mitochondrial function, tumor hypoxia, and glucose consumption in model tumors with Core B. 3) Establish the optimal level of radiosensitization in both subcutaneous and orthotopic model tumors treated with metabolic modifiers in collaboration with Project 1 and 4, and 4) Initiate a clinical trial that directly measures tumor oxygenation changes in patients with advanced Head and Neck Squamous Cell Carcinomas (HNSCC) with Project 2. It is important to note that because normal tissue is typically well oxygenated, systemic delivery of well tolerated metabolic modifiers will specifically radiosensitize tumors, without causing enhanced normal tissue toxicity.